The objectives of this research are to investigate the acute and chronic effects of antipsychotic drugs (APD) on dopamine (DA) metabolism in rat brain regions, particularly the frontal cortex. Previous work of the applicant indicated that the acceleration of DA metabolism persists in cortical regions whereas it subsides in subcortical regions during chronic administration of APD to monkeys or humans. Thus the cortical effects of APD have a similar time course with their therapeutic effects which also persist during chronic treatment. The hypothesis that different classes of DA receptor mediate the cortical and subcortical effects of APD will be tested by biochemical, pharmacological and behavioral tests. The pre- or postsynaptic location of cortical DA receptors will be investigated by use of specific chemical lesions. The sensitivity of adenylate cyclase to DA agonists will be tested in animals chronically treated with APD. The ability of DA agonists to alter DA metabolism will also be measured by radioenzymatic and mass-spectrometric methods. Differences between cortical and subcortical responses will be determined. The experiments will differentiate the biochemical and pharmacologic properties of cortical DA receptors from those of subcortical receptors. Because the former receptor class may mediate the therapeutic and the latter the toxic effects of APD, this research may provide the basis for the screening of agents with higher therapeutic specificity and lower toxicity than those currently available.